Iron in a variety of forms is administered for the treatment of iron deficiency and related disorders (e.g., anemia) as well as prophylactically to supply the minimum daily recommended allowance. A variety of iron compounds have been administered, including ferric and ferrous forms of elemental iron as salts, complexes, hydrates, chelates, and bound to polymer. Current oral iron preparations have low bioavailability and substantial side effects associated with them. Numerous formulation attempts have been made to create dosage forms that provide adequate iron absorption to treat deficiencies with less side effects. The side effects from oral administration primarily are a result of the large doses necessary to promote adequate absorption. It is likely that the presence of unabsorbed iron that remains in the gastrointestinal (GI) tract also significantly contributes to irritation, therefore side effects are also related to the poor bioavailability. The side effects include abdominal pain, heartburn, constipation, diarrhea, nausea, and vomiting. The inadequate absorption by oral delivery combined with poor compliance from the adverse effects on the GI tract means that in cases of substantial iron deficiencies, therapy must be carried out by parenteral injection, either intravenously or intramuscularly. Parenteral therapy is also associated with substantial side effects, including anaphylactic shock, injection site issues, hypotension, muscle cramps, dizziness, headache, graft complications, hypertension, chest pain, dysguesia, ear pain, and peripheral edema, as well as the cost and discomfort associated with injectable medication.
There is a need for improved oral formulations that achieve much better bioavailability. Such a formulation allows therapeutic doses to be given by a non-parenteral route while providing decreased side effects compared to present formulations. Such an improved formulation can be used to replace parenteral therapy, and further improve patient quality of life. By improving the oral bioavailability, the total dose and the residual amounts of iron in the GI tract will be lowered which will improve the side effect profile, improve compliance, and allow a therapeutic effect approaching that of the injectable products to be achieved. Oral doses can then be used to achieve the required blood concentrations and body loads which now can only be achieved via parenteral doses to improve hemoglobin and ferritin levels, e.g., in severely anemic patient.
Rapid release oral iron formulations are preferred since iron is best absorbed in the upper small intestine. Controlled and extended release formulations are not effective for iron since there is minimal lower intestinal and colonic absorption. The ideal site for absorption is the upper small intestine, where active transport/divalent metal transporters and favorable pH promote absorption.
WO 2005/041928 describes a composition comprising iron and a transport moiety, such as a fatty acid. The composition is prepared in a manner such that the iron and the transport moiety form a tight ion binding pair, i.e., a salt. Creation of new salt forms for iron has inherent issues associated with it, including the need to establish safety, stability, and commercial manufacturing procedures. Development of a formulation that can work with existing salts and/or chelates is much preferred.
There is a continuing need for development of novel pharmaceutical formulations of iron suitable for oral administration, which not only offer the convenience of oral dosing, but also provide increased bioavailability of iron without excessive side effects.